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United States Patent 3,145,210 ESTERS 0F Z-TRGIANOL Sydney Archer, Bethlehem, and Malcolm R. Bell, East Greenbush, NEIL, assignors to Sterling Drug Inc., New York, N.Y., a corporation of Delaware No Drawing. Filed Dec. 4, 1961, Ser. No. 157,018

14 Claims. (Cl. 260292) This invention relates to carboxylic acid esters of heterocyclic alcohols, and in particular is concerned with poly-substituted acetic acid esters of 2-tropano1 and homologs thereof, and with processes for their preparation.

One aspect of the invention is concerned with compounds having the formula wherein R is hydrogen, lower-alkyl or loWer-alkenyl; R is hydrogen or lower-alkyl; R is hydrogen, hydroXy, lower-alkoxy or lower-alkanoyloxy; and R and R are monocarbocyclic aryl, thienyl, pyridyl, cycloalkyl or cycloalkenyl. Also contemplated are compounds of the above formula wherein R and R in the moiety CR R are joined to form a fluorenyl, Xanthenyl, thiaxanthenyl or 9,10-dihydroanthracenyl ring as well as acid-addition and quaternary ammonium salts of the foregoing.

Another aspect of the invention is concerned with compounds having the formula wherein R is hydrogen, lower-alkyl or lower-alkenyl; R is hydrogen or lower-alkyl; and Z is l-(monocarbocyclic aryl)cycloalkyl, including the acid-addition and quaternary ammonium salts thereof.

In the above Formulas I and II, R stands for hydrogen or loWer-alkyl. The lower-alkyl groups preferably groups preferably have from one to four carbon atoms and thus include such groups as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and the like. The loweralkenyl groups preferably have from three to four carbon atoms and thus include such groups as allyl, methallyl, 2- butenyl and the like.

In the above Formulas I and II, R stands for hydrogen or lower-alkyl. The loWer-alkyl groups preferably have from one to four carbon atoms and thus include such groups as methyl, ethyl, propyl, isopropyl, butyl, isobutyl and the like.

In the above Formula I, R stands for hydrogen, hydroxy, lower-alkoxy or lower-alkanoyloxy. The loweralkoxy groups preferably have from one to four carbon atoms and thus include such groups as methoxy, ethoxy, propoXy, isopropoXy, butoXy, isobutoxy, and the like. The lower-alkanoyl groups preferably have from one to six carbon atoms and thus include such groups as formyloxy, acetoxy, propionoxy, butyryloxy, isobutyryloxy, valeryloxy, caproyloxy, and the like.

In the above Formula I, R and R stand for monocarbocyclic aryl, thienyl, pyridyl, cycloalkyl or cycloalkenyl. R and R can be the same or different. The

monocarbocyclic aryl groups are monocyclic aromatic groups of the benzene series and thus can be'phenyl rings optionally substituted by conventional groups inert under 3,145,210 Patented Aug. 18, 1964 the conditions of the processes used to prepare the compounds. A preferred class of monocarbocyclic aryl groups comprises phenyl and phenyl substituted by from one to three radicals selected from lower-alkyl, loweralkoxy, halogen (including fluorine, chlorine, bromine and iodine), lower-alkylmercapto and trifiuoromethyl. The lower-alkyl, lower-alkoxy and lower-alkylmercapto radicals contain from one to about four carbon atoms. thus including, inter alia, methyl, ethyl, propyl, isopropyl, butyl, methoxy, ethoxy, propoXy, isopropoxy, butoxy, methylmercapto, ethylmercapto and butylmercapto.

When R and/or R stand for thienyl or pyridyl, they can be in any of the various possible orientations, namely, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl and loWer-alkylated derivatives thereof.

When R and R stand for cycloalkyl or cycloalkenyl, the cycloalkyl groups preferably have from 5 t0 6 ring members and thus include cyclopentyl, cyclohexyl and lower-alkylated derivatives thereof; and the cycloalkenyl groups preferably have from 5 to 6 ring members and thus include l-cyclopentenyl, 2-cyclopentenyl, 3-cyclopentenyl, l-cyclohexenyl, Z-cyclohexenyl and 3-cyclohexenyl.

In the cases where R and R in compounds of Formula I are joined in the moiety CR R to form a fluorenyl, Xanthenyl, thiaxanthenyl or 9,10-dihydroanthracenyl ring, these merely represent variants of the compounds where R and R are both monocarbocyclic aryl wherein R and R are bridged by a bond (fluorenyl) or by an oxygen atom, a sulfur atom or a methylene group.

In the above Formula II, Z stands for a l-(monocarbocyclic aryl)cycloa1ky1 group. The monocarbocyclic aryl groups are of the same type as defined above for the monocyclic aryl groups R and R The cycloalkyl portion preferably has a 5 or 6 membered ring and includes cyclopentyl and cycloheXyl and loWer-alkylated derivatives thereof.

The compounds of the invention are prepared by one of the following methods:

1) The acid HOOCCR R R or HOOCZ is heated with Z-tropanol, or a homolog or analog thereof:

with 2-tropanol, or a homolog or analog thereof (III), 4

giving a hydrohalide of a basic ester of Formulas I or II. If this process is used, R is preferably limited to hydrogen or lower-alkoxy since a free hydroxy group would interfere with acid halide formation.

(3) A lower-alkyl ester of the acid or HOOCZ is heated with Z-tropanol, or a homolog or analog thereof (III), in the presence of a strong acid or strong'base;

eliminated, thus shifting the equilibrium in the direction 'of the desired ester 1; or II. The lower-alkyl group of the lower-alkyl ester preferably has from one tofabout This is an alcoholysis or ester interchange reaction wherein the more volatile alcohol is four carbon atoms, thus including such groups as methyl, ethyl, propyl, isopropyl and butyl. The reaction may be carried out in an inert solvent and occurs readily at temperatures between about 50 C. and 200 C.

The 2-tropanols (III); R is CH R is H) of both stereochemical configurations, 2a-tropanol and ZB-tropanol, are known substances, and esters of both isomers are contemplated by the invention.

Compounds of Formula III where R is hydrogen, loWer-alkyl other than methyl, or lower-alkenyl are prepared from the known 2-tropanols as follows: an ester of 2-tropanol is treated with cyanogen bromide in an inert solvent at about 50 C. During this process the N-methyl group is removed and replaced by a cyano group to give an 8-cyano-2-tropanyl ester. The latter, upon refluxing with concentrated hydrochloric acid is hydrolyzed and decarboxylated to give 2-nortropanol (R is'I-I). The 2-nortropanol can then be alkylated with any desired lower-alkyl or lower-alkenyl group by heating it with a lower-alkyl halide or a lower-alkenyl halide in the presence'of an acid acceptor such as sodium carbonate.

Compounds of Formula III where R is lower-alkyl can beprepared by treating the known '2-tropanone with a lower-alkyllithium. If desired, the resulting 2-loweralkyl-2-tropanol can be further altered to change the nature of the group R as described above.

The compounds of this invention are the free bases of the Formulas I and II and the acid-addition and quaternary ammonium salt forms thereof. The acid-addition salts are prepared by causing the free base to react with a strong inorganic or organic acid, usually in an inert solvent or reaction medium. Examples of appropriate acids include hydrochloric, hydrobromic, sulfuric, phosphoric, citric, tartaric, quinic, benzenesulfonic acid, and the like.

The quaternary ammonium salts of the compounds of the invention are prepared by causing a free base to react with an ester of a strong inorganic or organic sulfonic acid, said ester preferably having a molecular weight less than about 200. A particularly preferred class of esters, because of their ready availability, are lower-alkyl, lower- -alkenyland monocarbocyclic aryl-lower-alkyl esters, for example, methyl iodide, ethyl iodide, ethyl bromide, propyl bromide, butyl bromide, allyl bromide, methyl sulfate, methyl benzenesulfonate, methyl p-toluenesulfonate, benzyl chloride, o-chlorobenzyl chloride, and the like. The reaction of the free base and the quaternizing agent takes place upon simple admixture of the components, preferably in the presence of an inert organic solvent, although heating may be applied to accelerate the reaction.

The acid-addition and quaternary ammonium salts preferably have anions which are pharmacologically acceptable, that is, the anions do not appreciably increase the toxicity of the compound as a whole toward animal organisms. Such anions include, for example, the chloride,, bromide, iodide, sulfate or acid sulfate, methanesulfonate, benzenesulfonate, and the like. Salts having toxic anions are, however, useful in that they serve as characterizing derivatives of the free base and serve as intermediates for non-toxic quaternary salts by conventional ion exchange reactions. All acid-addition salts, regardless of the nature of the anions, are useful as intermediates in the purification of the free bases.

Pharmacological evaluation of the compounds of Formulas I and II has demonstrated that they possess pharmacodynamic activity. In particular they possess anticholinergic activity and have the ability to reverse the decrease in spontaneous activity in mice brought about by 'tremorine (1,4-dipyrrolidino-2-butyne).

The structure of the compounds was established by the methods of preparation and by the fact that the results of chemical analysis were in agreement with the expected structures.

The following examples will further illustrate the invention without the latter being limited thereby.

EXAMPLE 1 2a-Tr0panyl Belzzilate [1; R is CH R is H, R is OH (or-configuration), R and R are C H A mixture of 3.00 g. (0.0213 mole) of Zu-tropanol, 5.41 g. (0.0223 mole) of methyl benzilate and 250 ml. of heptane was refluxed for one hour under a Dean-Stark separator. There was then added 0.115 g. (0.00213 mole) of sodium methoxide, and the mixture was refluxed for twenty hours and allowed to stand at room temperature for five days. The reaction mixture was diluted with an equal volume of ether and extracted with a solution of 3 ml. of concentrated hydrochloric acid in 50 ml. of water. The aqueous layer was separated and cooled to 5 C., and the resulting precipitate was collected by filtration to give 5.3 g. of Za-tropanyl benzilate in the form of its hydrochloride salt, colorless needles, M.P. 228.2-230.6 C. (dec.) (corn) when recrystallized from water.

An aqueous solution of the hydrochloride salt was converted to the free base by adding excess sodium hydroxide solution. The product was extracted with methylene dichloride, and the extracts were dried over anhydrous sodium sulfate and concentrated to dryness. The residue was dissolved in benzene and chromatographed on a column of magnesium silicate. The product was eluted with benzene and recrystallized from hexane-to give 2a-tropanyl benzilate, colorless prisms, 'M.P. 113.21 14.0 C. (corn). In another preparation a sample of 2a-tropanyl 'oenzilate was obtained having the M1. 127-l33 C. (uncorr.), the difference in melting point probably being due to polymorphism.

Za-tropanyl benzilate in the form of itshydrochloridc salt, when tested for mydriasis in the mouse, by the method described by Long et al., J. Pharmacol. Exptl. Therap. 117, 29 (1956), had an ED value of 0.044 ing/kg. in terms of the free base; and when measured for its ability to reverse the decrease in spontaneous motility in mice produced by 10 mg./kg. of tremorine, the compound was found to have a normalizing dose (ND) of 0.025 rug/kg. The intravenous toxicity of Za-tropanyI benzilate hydrochloride in the mouse was determined and anLD 50 value of 2912.9 ing/kg. was found.

A solution of 0.30 g. of Zea-lI'OpZtIlYl benzilate in 50 ml. of absolute ethanol was cooled to 0 C. and methyl bromide gas was passed through the solution for thirty minutes. The mixture was allowed to stand at room temperature for four days and then concentrated to dryness. The residue was crystallized first from acetone and then from isopropyl alcohol to give 2rx-tropanyl benzilate in the form of its methobro'mide salt, MP. 224.7-225.40 C. (dec.) (corn).

2u-tropanyl benzilate in the form of its methobromide salt was found to have a mydriatic ED value of 0.019 nag/kg.

In similar fashion 2a-tropanyl benzilate can be treated with ethyl iodide, allyl bromide, methyl sulfate, benzyl chloride, or o-chlorobenzyl chloride to give, respectively, the ethiodide, allobromide, methosulfatc, benzochloride, or o-chlorohenzochloride salts of Za-tropanyl benzilate.

EXAMPLE 2 free base was dissolved inether and treated with an excess of an ether solution of p-toluenesulfonic acid monohydrate. After standing for three days at 0 C. the solid product'was collectedby filtration and recrystallized from an ethanol-ether mixture to give Zfi-tropanyl benzilate in the form of its p-toluenesulfonate salt, M.P. 237-23840 C. (corr.).

2,8-tropanyl benzilate in the form of its p-toluenesulfonate salt was found to have a mydriatic ED value of 1.34 mg./kg. and a tremorine normalizing dose of 1.5 mg./l g.

25-tropanyl benzilate can be treated with hydrobromic acid, hydrofluoric acid, hydriodic acid, nitric acid, sulfuric acid, phosphoric acid, acetic acid, citric acid, tartaric acid, lactic acid, quinic acid, naphthalene-l-sulfonic acid, or ethanesulfonic acid to give, respectively, the hydrobromide, hydrofiuoride, hydriodide, nitrate, sulfate (or bisulfate), phosphate (or acid phosphate), acetate, citrate (or acid citrate), tartrate (or bitartrate), lactate, quinate, naphthalene-l-sulfonate, or ethanesulfonate salt of Zfl-tropanyl benzilate.

The hydrofluoride salt of ZB-tropanyl benzilate can be converted to the hydrochloride salt of ZB-tropanyl benzilate by contacting it with an ion exchange resin saturated with chloride ion.

EXAMPLE 3 2ctropanyl diphenylmethoxyacetate [1; R is C R is H, R is OCT-1 R and R are C 11 was prepared from 2a-tropanol and methyl diphenylmethoxyacetate in the presence of sodium methoxide according to the procedure described above in Example 1. The compound was obtained in the form of its p-toluenesulfonate salt, colorless prisms, M.P. 126.6-127.7 C. (corr.) when recrystallized from acetone.

2a-tropanyl diphenylmethoxyacetate in the form of its p-toluenesulfonate salt was found to have a mydriatic E13 value of 2.95 mg./kg. and a tremorine normalizing dose of 4.1 mgJkg.

EXAMPLE 4 2a-tropanyl cyclopentyl(2-thienyl)glycolate [1; R is CH R is H, R is OH, R is C 11 R is Z-C H S] was prepared from Zoe-tropanol and methyl cyclopentyl(2- thienyl)glycolate in the presence of sodium methoxide according to the procedure described above in Example 1. The compound was obtained in the form of its p-toluenesulfonate salt, M.P. 134.8-136.4 C. (corr.) when recrystallized from an acetone-ether mixture.

The intermediate. methyl cyclopentyl(2-thienyl)glycolate was prepared by esterifying the free acid with methanol in the presence of sulfuric acid. The methyl ester had the B.P. 130-134 C. (0.08 mm), n =1.5633.

EXAMPLE '5 '2a-tropanyl diphenyl(n-propoxy)acetate [1; R is CH R is H, R is OCH CH C1-1 R and R are C H was prepared from Za-tropanol and methyl diphenyl(n-propoxy)acetate in'the presence of sodium methoxide according to the procedure described above in Example 1. The compound was obtained in the form of its p-toluenesulfonate salt, M.P. 1636-46513 C. (corr.) when recrystallized from ethyl acetate.

The intermediate methyl diphenyl(n-pr opoxy)acetate was prepared as follows: bromodiphenylacetyl bromide was caused to react with n-propyl alcohol to give n-propyl diphenyl(n-propoxy)acetate, B.P."139-l44 C. (0.4-0.5 mm.) n =1.5309. The latter was hydrolyzed by heating with potassium hydroxide in n-propyl .alcohol to give diphenyl(n-propoxy)acetic acid, M.P. 109113 C. The free acid was esterified with diazomethane to give the methyl ester, B.P. 111 C. (0.025 mm.), 'n =1.5427.

EXAMPLE 6 Za-trcpanyl-di-(Zthienyl) glycolate [1; R is CH R is H, R is OH, R and R are 2-C H S] was prepared from '2a-tropanol and methyl di-(2-thienyl)glycolate 5 199.2-202.0 C. (dec.) (corr.) when recrystallized from ethyl alcohol.

EXAMPLE 7 Za-tropanyl phenyl(2-thienyl)glycolate [1, R is CH R is H, R is OH, R is C 11 R is 2-C H S] was prepared from ZOL-lI'OPfll'lOl and methyl phenyl(2-thienyl) glycolate [B.P. 147147.5 C. (0.08 mm), n =1.5855] in the presence of sodium methoxide according to the procedure described above in Example 1. The compound was isolated first in the form of the hydrochloride salt, M.P. 184-l88 C. (dec.) (uncorr.) when recrystallized from isopropyl alcohol, and then was converted to the free base, M.P. 131.0-141.0 C. (corr.) when recrystallized from acetone.

2a-tropanyl phenyl(2-thienyl)glycolate in the form of its hydrochloride salt was found to have a mydriatic ED Value of 19.9 micrograms/ kg. and a tremorine normalizing dose of 13.5 micrograms/kg.

EXAMPLE 8 Za-TrOpanyZ 1-Phenylcyclopentanecarhoxylate [11; R is CH R is H, Z is 1-phenylcyclopentyl1 A solution of 1.41 g. (0.01 mole) of 2a-tropanol and 4.36 g. (0.02 mole) of ethyl l-phenylcyclopentanecarboxylate in ml. of xylene was refluxed for one hour under a water separator. Sodium (0.02 g., 0.001 mole) was added and the mixture was refluxed for about fifteen hours. Most of the xylene was then distilled off over a period of about two hours until the internal temperature was about C. The reaction mixture was cooled, diluted with ether and extracted several times with dilute hydrochloric acid (3 ml. of concentrated hydrochloric acid in 20 ml. of water). The aqueous phase was extracted with ether and made basic with 10% sodium hydroxide solution. The free base was extracted with ether, and the ether extracts were dried and concentrated to dryness. The residue was dissolved in ethanol, excess hydrochloric acid was added and the solution cooled to -10 C., whereupon there separated 2.65 g. of 2a-tropanyl 1-phenylcyclopentanecarboxylate in the form of its hydrochloride salt, light tan needles, M.P. 186.8192.0 C. (corr.) when recrystallized first from acetone and then from a methanol-ether mixture.

According to the procedures described hereinabove 2oztropanol can be caused to react with methyl dicyclohexylacetate, methyl cyclohexylphenylacetate, methyl (2-cyclohexenyl)phenylacetate, methyl 9-fluorenecarboxylate,

methyl di-(4-methoxy)benzilate, methyl 9-xanthenecarboxylate, methyl 10-thiaxanthenecarboxylate, methyl 9-(9, 10)-dihydroantlracenecarboxylate, methyl 1-(o-tolyl)cyclopentanecarboxylate, methyl 1-(m-methoxyphenyl)cyclopentanecarboxylate, methyl l-phenylcyclohexanecarboxylate, methyl 1-phenyl-2-rnethylcyclohexanecarboxyl ate, methyl (Z-cyclopentenyl) (2cyclohexenyl)acetate, or methyl phenyl(2-pyridyl)acetate, to give, respectively, 20:- tropanyl dicyclohexylacetate [1; R is CH R and R are H, R and R are C H 2or-tropanyl cyclohexylphenylacetate [1; R is CH R and R are H, R is C 11 R is C l-I Za-tropanyl (Z-cyclohexenyl)phenylacetate [1; R is CH R? and R are H, R is C H R is Z-cyclohexenyl], 2a-tr0panyl 9-fluorenecarboxylate [1; R is CH R and R are H, CR R is 9-fluorenyl], Za-tropanyl di- (4'-methoxy)benzilate [1; R is CH R is H, R -is OH,

R and R are 4-CH 0C H 2a-tropanyl 9-xanthenecar- I boxylate [1; R is CH R and R are H, CR R is 9-xan-' thenyl], 2a-tropanyl 10-thiaxanthenecarboxylate [1; R is CH R3 and R are H, CR R is 10-thiaxanthenyl], 20atropanyl -1-(m-methoxyphenyl)cyclopentanecarboxylate [11; R is CH R is H, Z is l-(m-methoxyphenyl)cycloe pentyl], Za-tropanyl 1-phenylcyclohexanecarboxylate [11;

R is CH R is H, Z is l-phenylcyclohexyl], Za-tropanyl 1-phenyl-2-methylcyclohexanecarboxylate [11; R is CH R is H, Z is 1-phenyl-2-methylcyclohexyl], 2zx-tropanyl (Z-cyclopentenyl) (2-cyclohexenyl)acetate [1; R is CH R and R are H, R is 2-cyclopentenyl, R is 2-cyclohexenyl], or 2rx-tropanyl phenyl(2-pyridyl)acetate [1; R is CH;,, R and R are H, R is C 11 R is C H N].

The methyl esters used as starting materials are prepared by treating the known free acids with an ethereal solution of diazomethane.

EXAMPLE 9 2a-Tr0panyl Acetoxydiphenylacetate [1; R is CH R is H, R is CH COO, R and R are C 11 2a-tropanyl benzilate hydrochloride (Example 1) (2.0 g.) was suspended in methylene dichloride and dilute ammonium hydroxide solution was added until the acidaddition salt had been completely converted to the free base. The aqueous and organic layers were separated, the aqueous layer was extracted with methylene dichloride, and the combined methylene dichloride solutions were dried over magnesium sulfate and concentrated to dryness. The residue was refluxed with 20 ml. of acetic anhydride for ten minutes, and the mixture concentrated on a steam bath in vacuo. The residue was treated with hydrochloric acid (1 part of concentrated hydrochloric acid and 3 parts of water), and the mixture extracted with ether. The aqueous layer was separated, made basic with ammonium hydroxide and extracted with methylene dichloride. The extracts were washed with water, dried over magnesium sulfate and concentrated to dryness. The residue was dissolved in ether and an excess of ethereal hydrogen chloride added. The product which separated was collected and recrystallized from isopropyl alcohol to give 2a-tropanyl acetoxydiphenylacetate in the form of its hydrochloride salt, M1. 1912-1940 C. (dec) (corn).

By replacing the acetic anhydride in the foregoing preparation by propionic anhydride, butyric anhydride or caproic anhydride there can be obtained, respectively, 20:- tropanyl propionoxydiphenylacetate [1; R is CH R is H, R is CH CH COO, R and R are C 11 2u-tropanyl butyryloxydiphenylacetate [1; R is CH R is H, R is CH CH CH COO, R and R are C 11 or 2a-tropanyl caproyloxydiphenylacetate [1; R is CH R is H, R is I{4 and R5 are C6H5].

EXAMPLE l 2a-Tr0pa/zyl Dl'phenylacetate [1; R is CH R and R are H, R and R are C H Diphenylacetic acid (2.96 g.) and 50 ml. of thionyl chloride were refluxed for one hour. The excess thionyl chloride was removed in vacuo, and the residue was dissolved in ml. of methylene dichloride and added to a solution of 1.00 g. of Za-tropanol in ml. of pyridine. The mixture was allowed to stand at room temperature for about fifteen hours and then heated for thirty minutes on a steam bath while allowing the methylene dichloride to escape. The reaction mixture was concentrated to dryness on a steam bath, and the residue was shaken with ether and ml. of water containing 4 ml. of concentrated hydrochloric acid. The aqueous phase was extracted twice with ether and made basic with sodium hydroxide. The basic product was extracted with methylene dichloride and the extracts were dried and concentrated. The residue was made freeof pyridine by heating it at 100? C. (0.08 mm.) for thirty minutes and was distilled at ISO-170 C. (0.1 mm.). The distillate was dissolved in an ethanolether mixture, and an excess of a solution of hydrogen bromide in acetic acid was added. The crystalline product which separated was collected and recrystallized from an ethanol-ether mixture to give ZCL-tl'DPHI'lYl diphenylac-etate in the form of its hydrobromide salt, M.P. 209.82l1.8 C. (corn).

3 EXAMPLE 11 (a) 2-Methyl-2-Tropanol [111; R and R are CH To a stirred mixture of 5.5 g. (0.79 mole) of lithium wire in 200 m1. of ether was added 40 drops of a solution of 51 g. of methyl iodide in 200 ml. of ether. The mixture was warmed to initiate reaction and then cooled in ice. The remainder of the ether solution of methyl iodide was added over a period of twenty minutes and the mixture was refluxed for thirty minutes. The resulting mixture was cooled in an ice bath and 10 g. (0.072 mole) of 2-tropanone in 50 ml. of ether was added over a period of twenty minutes. The reaction mixture was refluxed for thirty minutes, allowed to stand at room temperature for about fifteen hours and then hydrolyzed by careful addition of water. The aqueous layers were separated, saturated with potassium carbonate and extracted with methylene dichloride. The methylene dichloride extracts were combined with the original ether layer, dried over magnesium sulfate and concentrated to dryness. The residue was recrystallized from hexane to give 5.8 g. of Z-methyl- Z-tropanol, M.P. 9394 C. (uncorr.). The infrared spectrum indicates the presence of a free hydroxy group and that the compound is the equatorial alcohol, 2,3-methyl-2tx-tropanol. A portion of the free base was converted to its p-toluenesulfonate salt, M.P. 133135 C. (uncorr.) when recrystallized from an ethyl acetate-acetone mixture.

(b) Zfi-methyI-Za-zropanyl benzilate [1; R and R are CH R is OH, R and R are C H can be prepared from 2fi-methyl-2a-tropanol and methyl benzilate according to the procedure described above in Example 1.

Similarly, 2e-methyl-2a-tropanol reacts with methyl 1- phenylcyclopentanecarboxylate to give 2fl-methy1-2atropanyl 1-phenylcyclopentanecarboxylate [11; R and R are CH Z is l-phenylcyclopentyl].

By analogous procedures, 2-tropanone can be caused to react with butyllithium to give 2 8-butyl-2a-tropanol, and the latter esterified with methyl benzilate to give 25- butyl-Za-tropanyl benzilate [1; R is CH R is CHg, R is OH, R and 5 are C H EXAMPLE 12 (a) 2a-tropanyl acetate gradually added to a benzene solution of a molar excess of cyanogen bromide in benzene solution at a temperature of about 50 C. and the solution cencentrated gives 8 cyano-2a-nortropanyl acetate. 8-cyano-2ot-nortropanyl acetate when refluxed with concentrated hydrochloric acid for several hours, the mixture made basic with potassium carbonate, and the product isolated, gives 2a-hydroxynortropane [111; R and R are H].

By a similar procedure 2fi-methyl-2wtropanol (Example 11a) in the form of its acetate ester is converted to Zfl-methyl-h-hydroxynortropane [111; R is H, R is CH A mixture of Za-hydrOXynortropane and a molar ex cess of allyl bromide in 'n-butyl alcohol in the presence of sodium carbonate refluxed for about fifteen hours, and the product isolated, gives S-allyl-2a-hydroxynortropane [111; R is CH =CHCH R is H].

Similarly, 2e-hydroxynortropane reacts with isopropyl bromide or n-butyl bromide to give 8-isopropyl-2u-hydroxynortropane [111; R is (CH CH, R is H] or 8-(n-butyl)-2a-hydoxynortropane [111; R is Cl-I CH CH CH R is H]; and ZB-rnethyl-h-hydroxynortropane reacts with allyl bromide to give 8-allyl-2fi-methyl-2a-hydroxynortropane [111; R is CH CHCH R is CH (b) According to the procedure described in Example 1, methyl benzilate can be caused to react with Zen-hy- 1 droxynortropane, 2;? methyl 2a hydroxynortropane,

8 allyl 2a hydroxynortropane, 8 isopropyl 2a- .hydroxynortropane, 8 (n butyl) 2o: hydroxynortropane, or 3 2111yI-Z/B-methyI-Za-hydroxynortropane, to give,

-respectively, 2a-nortropanyl benzilate [1; R and R are H, R is OH, R and R5 are C 11 2,6-methyl-2a-nortroaraaaro and R are C 11 8-allyl-2a-nortropanyl benzilate [1; R is CH CHCH R is H, R is CH, R and R are C 11 8-isopropyl-2u-nortropanyl benzilate [1; R is (CH CH, R is H, R is OH, R and R are C 11 8- (n butyl) 20c nortropanyl benzilate [1; R is CH CH CH CH R is H, R is OH, R and R are C H or 8-allyl-Zfl-methyl-Za-nortropanyl benzilate [1; R is CH =CHCH R is CH R is OH, R and R 31 6 C6H5].

Similarly, Zoe-hydroxynortropane and 8-allyl-2a-hydroxynortropane each reacts with methyl l-phenylcyclopentanecarboxylate to give, respectively, 2et-nortropanyl 1-phenylcyclopentanecarboxylate [11; R and R are H, Z is l-phenylcyclopentyl] and 8-allyl-2a-nortropany1 1- phenylcyclopentanecarboxylate [11; R is CH CHCH R is H, Z is l-phenylcyclopentyl].

We claim:

1. A compound selected from the group consisting of (A) compounds of the formula wherein R is a member of the group consisting of hydrogen, lower-alkyl and loWer-alkenyl; R is a member of the group consisting of hydrogen and lower-alkyl; R is a member of the group consisting of hydrogen, hydroxy, lower-alkoxy and lower-alkanoyloXy; and R and R are members of the group consisting of monocarbocyclic aryl, thienyl, pyridyl, cycloalkyl having from 5 to 6 ring members and cycloalkenyl having from 5 to 6 ring members; (B) compounds of the above formula wherein R and R in the moiety CR R are joined to form a member of the group consisting of fluorenyl, Xanthenyl, thiaxanthenyl and 9,10-dihydroanthracenyl; (C) acid-addition salts of (A) and (B); and (D) lower-alkyl, loweralkenyl and monocarbocyclic aryl-lower-alkyl quaternary ammonium salts of (A) and (B); monocarbocyclic aryl in each instance being a member of the group consisting of phenyl and phenyl substituted by from one to three radicals selected from the group consisting of lower-alkyl, lower-alkoxy, halogen, lower-alkylmercapto and trifluoromethyl,

2. A compound of the formula wherein R is a member of the group consisting of hydrogen, lower-alkyl and lower-alkenyl; R is a member of the group consisting of hydrogen and lower-alkyl; and Z is l-(monocarbocyclic aryl)cycloalkyl wherein the cycloalkyl has from 5 to 6 ring members; (B) acid-addition salts thereof; and (C) lower-alkyl, lower-alkenyl and monocarbocyclic aryl-lower-alkyl quaternary ammonium salts thereof; monocarbocyclic aryl in each instance being a member of the group consisting of phenyl and phenyl substituted by from one to three radicals selected from the group consisting of lower-alkyl, lower-alkoxy, halogen, lower-alkylmercapto and trifiuoromethyl.

14. 2a-tropanyl 1-phenylcyclopentanecarboxylate.

References Cited in the file of this patent UNITED STATES PATENTS 2,748,133 Karrer May 29, 1956 2,800,476 Stoll et a1 July 23, 1957 2,921,938 Wetterau Jan. 19, 1960 OTHER REFERENCES Ayer et al.: J. Am. Chem. Soc., Vol. 80, p. 6146 (1958).

Bell et al.: J. Am. Chem. Soc., Vol. 80, p. 6147 (1958).

UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No. 3, 145,210 August 18 1964 Sydney Archer et all,

It is hereby certified that error appears in the above numbered patent requiring correction and that the said Letters Patent should read as corrected below.

Column 1, linest44 and 45 for "hydrogen or lower-alkyl" read hydrogen, lower-alkyl or lower-alkenyl line 46 strike out "groups preferably"; column 5 line 22 for "R is C read R is CH Signed and sealed this 30th day of March 1965..

SEAL) Ittest:

ERNEST W. SWIDER EDWARD J. BRENNER nesting Officer Commissioner of Patents 

1. A COMPOUND SELECTED FROM THE GROUP CONSISTING OF (A) COMPOUNDS OF THE FORMULA 